I am a writer, scientist, and educator who focuses on how we think about how we think. Here you'll find reports on the latest brain-related research, analyses of the social and biological aspects of brain health, and some opinionating. My work has appeared at the New York Times Motherlode blog, Forbes, Slate, Grist, The Scientist, Scientific American guest blogs, MIT Tech Review, American Scientist, The Scientist, Backpacker, Texas Parks and Wildlife Magazine, and in other local and regional publications.

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Influenza, Fever, And Autism: How Much Should You Worry?

"A child with autism (three years old) pointing to the fish in an aquarium." The photo demonstrates a controlled randomized test by Kasari, Stephanny Freeman and Tanya Paparella to determine whether intensive training in sharing attention (in this case, pointing at fish) and pretend playing can lay the groundwork for the acquisition of language skills and subsequent normal development. (Photo credit: Wikipedia)

It looks like big news: flu or prolonged fever or taking antibiotics linked to autism in large study of 98,000 children. But let’s take a closer look. First, the story, from NBC, which aired a report on Today:

Doctors trying to find some of the causes of autism put another piece into the puzzle on Monday: They found women who had flu while they were pregnant were twice as likely to have a child later diagnosed with autism. Those who had a fever lasting a week or longer — perhaps caused by flu or maybe by something else — were three times as likely to have an autistic child.

The study of 96,000 children in Denmark raises as many questions as it answers.

This story doesn’t link to the study itself–something that science consumers would very much like articles to do–so you can find the abstract here; the article is paywalled.

What the authors did was take self reports from pregnant women during and after pregnancy in two telephone interviews. That’s issue number one: It’s self report, which is a cost-effective way to get information, particularly from a large population, but also is inherently unreliable. There was no clinical confirmation of an influenza infection, and people notoriously think they have the flu when in fact, they have a bad version of the “common cold.” ETA: I also should note that the questions they asked the women never referred specifically to influenza.

The second issue has to do with the many statistical comparisons the authors made using the information they received. The more comparisons researchers make, the greater the chance that something will look significant when it’s really just a chance result. Consider that famous p value cutoff of 0.05. That means that one time in twenty that value turns up, it’s misleading in implying significance. The more comparisons you make, the more likely some difference will look important when it’s not. It’s possible to make certain adjustments to make up for this increasing likelihood, but the authors of the current Danish study did not make these adjustments, arguing that they didn’t need to because it is “exploratory.” ETA: In the end, they performed 106 comparisons and say in their paper that none of their statistically significant findings would have survived these adjustments and remained significant.

I’m not just making up these limitations. The authors themselves mention them. They write in their paper that “misreporting of influenza is likely to be considerable.” They also note in the last sentence of their abstract that “The results may be due to multiple testing; the few positive findings are potential chance findings.”

Results from other groups on the outcomes of fever or influenza infection during pregnancy are mixed. Some studies find no connection between infection during pregnancy and autism while others do. In fact, another Danish study from this same group looking at maternal infections across pregnancy found no association between any maternal infection and an autism diagnosis in the child. They did find a limited increased risk of having an autistic child for pregnant women admitted to the hospital for viral infection during the first trimester or having a bacterial infection in the second trimester.

In another study whose authors did confirm clinical influenza (rather than relying solely on self report), the researchers found no increased risk for having a child with autism for women who’d had influenza during pregnancy. Like the current findings, though, this group did confirm an increased risk for having a child with autism or developmental delay for women who had experienced “fever” during pregnancy. These authors also found that the risk fell to near-normal odds, however, if women took anti-fever medication. In this new Danish study, maternal fever in general, even very high fever, was not linked to an increased autism risk in the child, but a fever lasting seven days or longer was.

Other pathogens are known to affect prenatal brain development, so it’s not novel to think that something as potentially virulent as an influenza virus could. But the information so far is mixed. It may be that a prolonged fever has an effect, but whether that’s the fever or the agent causing the fever is an open question.

There’s one thing that was clinically confirmed in this study that no one seems to have highlighted. In this population of 98,000 children born from 1997 to 2003, 976 were diagnosed with autism. That means 1% of this population, currently ages 8 to 14, has autism, a value very close to those emerging in many studies and to the latest estimates for prevalence among 8-year-olds in the United States.

Finally, if you’re pregnant and worried, you can do three things. First, you can get a flu shot, which is recommended anyway for most pregnant women [PDF]. Second, you can find out more about autism, particularly from autistic adults, and learn that having an autistic child is not inevitably a tragic horrorshow that you need to stress about before you even know you’d have one [*see related comment below]. Third, you can enjoy the math in this quote via WebMD from study author Hjordis Osk Atladottir, who notes that “98% of the women in this study who experienced influenza or fever or took antibiotics during pregnancy did not have children with autism.” In the NBC story, he’s quoted as saying 99% didn’t have a child with autism.

You can count me among the “flu-during pregnancy” population. I spiked a four-day 105 fever because of clinically proven influenza in my first trimester of pregnancy with our second son. But he’s not the son who’s autistic.

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For crying out loud, will someone, somewhere, somehow, write a filter that will killfile the inevitable Anne Daschel copy/paste attack? Please! This person will be granted +1000000 karma, and I will personally throw a cream pie in the face of anyone that they desire and put the resulting video on youtube.

That being said, it seems very likely from repeated findings in the animal realm that the mechanism of action is not the pathogen itself, but rather, the bodies response to said pathogen. As we can see in this study, any effect was mitigated through the use of antipyretics, another finding with broad support in animal models of maternal or early postnatal immune activation with subsequent neurodevelopmental outcomes. Little brains are performing a tightly choreographed dance and some of the molecules used in signaling the immune system also appear to be have functions during development.

This is also consistent with what we seem to observe with lots of other maternal conditions that seem to be associated with autism like obesity or asthma; an increase in immune molecules associated with inflammation.

FWIW – My wife was sick damn near her entire fifth month of pregnancy with our version of Kid Autism.

Emily, I love your take on this, and you have a wonderful way of translating these issues to the lay reader. I do want to play devil’s advocate with familywise adjustment of alpha, though. The penalty for number of comparisons should be *for comparisons of the same thing*. If you have 20 indicators of autism, and a p < .05 criterion, chances are you will find the link between fevers and one of them significant, and so you sweep the others under the rug. If you're looking at fevers and 20 (or 106) different outcomes, then adjustment makes no sense. See this excellent piece by Dan O'Keefe: https://netfiles.uiuc.edu/dokeefe/www/OKeefe03againstHCR.pdf

Thank you, and thanks for the link to the paper. I coulda used that argument back in 1996 for a specific reviewer.

The authors seemed to think that was relevant, so I included it. I think that part of it is because this wasn’t an a priori designed study, so basically, anything they looked at was a fishing expedition of sorts, hence their also having run corrections for multiple comparisons but not reporting them. Frankly, because of the arbitrariness of cutoffs and the age-old issue of clinical vs statistical relevance, I don’t think that issue is the big one here. The big one, especially in terms of reportage on this story, is that they didn’t ask specifically about influenza and have no clinical confirmation of cases. Without that, even unequivocal statistical relevance remains in question.

I realize that. The question is, why didn’t the doctors file a VAERS report without me insisting upon it? They are legally required to do so. If I had not insisted on it, and continued to follow-up on it, I doubt it would have been reported. As I noted, doctors should be totally objective in trying to find the cause and the treatment of an illness. My experience was that the doctors were everything but objective. Everytime I brought up a potential link between the flu vaccine and my wife’s condition, it was met with defensiveness. That is not good medicine and defensive reactions suggest that a person has something to hide. I am not a anti-vaccine person, I am just an average guy who battled for my wife to receive treatment that saved her life.

I have had experiences with doctors that are as varied as they can be. Some are careful, assiduous, listening, and attentive. Some have been extraordinarily dismissive and careless, on more than one occasion to the detriment of successful care. In these latter situations, without my having been persistent or having some sufficient “insider” awareness to pursue certain paths, things could have gone badly. I am a member of one patient community, and their personal experiences with physicians span a similar spectrum. In other words, doctors are people, and their skill, personalities, interest, competence, and bedside manner all vary as much as people themselves do.